Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.

Center for Hematologic Malignancies Memorial Sloan Kettering Cancer Center New York NY USA

Children's Hospital Paediatric Oncology Skåne University Hospital Lund Sweden

Clinical Cooperation Unit Neuropathology German Consortium for Translational Cancer Research Heidelberg Germany

Clinical Cooperation Unit Pediatric Oncology and German Consortium for Translational Cancer Research Heidelberg Germany

Computational Oncology Service Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY USA

Department of Clinical Medicine Rigshospitalet University of Copenhagen Copenhagen Denmark

Department of Neuropathology Heidelberg University Hospital Heidelberg Germany

Department of Neuropathology University Giessen Giessen Germany

Department of Oncology and Haematology Perth Children's Hospital Perth WA Australia

Department of Oncology Hematology Cell Therapy Gene Therapy and Haemopoietic Transplant Bambino Gesù Children's Hospital IRCCS Rome Italy

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Pathology Brain Tumor Center Amsterdam University Medical Center Amsterdam Universities Medical Centers VUmc Amsterdam The Netherlands

Department of Pathology CHU Gabriel Montpied Clermont Ferrand France

Department of Pathology IUCT Oncopole Toulouse University Hospital Toulouse France

Department of Pathology Lille University Hospital Lille France

Department of Pathology NYU Langone Health New York NY USA

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine University Hospital Motol Charles University Prague Czech Republic

Department of Pediatric Oncology and Hematology Freie Universität Berlin Humboldt Universität Zu Berlin and Berlin Institute of Health Charité Universitätsmedizin Berlin Berlin Germany

Department of Pediatric Oncology Hematology and Immunology Heidelberg University Hospital Heidelberg Germany

Department of Pediatrics Albert Einstein College of Medicine Bronx New York USA

Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics Medical University of Vienna Vienna Austria

Department of Pediatrics Children's Cancer Centre Royal Children's Hospital Murdoch Children's Research Institute University of Melbourne Melbourne VIC Australia

Department of Pediatrics Memorial Sloan Kettering Cancer Center New York USA

Division of Cancer Sciences University of Manchester Manchester UK

Division of Molecular Pathology Institute of Cancer Research London UK

Division of Neuropathology and Neurochemistry Department of Neurology Medical University of Vienna Vienna Austria

Division of Neuropathology NYU Langone Health New York NY USA

Division of Paediatrics Department of Haematooncology University Medical Center Ljubljana Ljubljana Slovenia

Division of Pediatric Glioma Research Im Neuenheimer Feld 280 69120 Heidelberg Germany

Division of Pediatric Hematology and Oncology University Medical Center Göttingen Gottingen Germany

Division of Pediatric Hematology Oncology 1st Department of Pediatrics National and Kapodistrian University of Athens Athens Greece

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany

Faculty of Medicine Heidelberg University Heidelberg Germany

Frankfurt Cancer Institute Frankfurt Germany

German Cancer Consortium Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Heidelberg Germany

Human Molecular Genetics de Duve Institute Université Catholique de Louvain Brussels Belgium

INSERM U1037 Team 11 Cancer Research Center of Toulouse Toulouse France

INSERM U837 UMR S1172 Centre de Recherche Jean Pierre Aubert Team 1 Lille France

Institute of Neuropathology Brain Tumor Reference Center of the Society for Neuropathology and Neuroanatomy University of Bonn Medical Center Bonn Germany

Isabel Rapin Division of Child Neurology Albert Einstein College of Medicine Bronx New York USA

John Hunter Children's Hospital Newcastle Newcastle NSW Australia

Laboratory of Pathology University Hospital of Clermont Ferrand Clermont Ferrand France

Marie Josée and Henry R Kravis Center for Molecular Oncology Memorial Sloan Kettering Cancer Center New York NY USA

Neurological Institute University Hospital Frankfurt Germany

Paediatric and Adolescent Medicine Department of Clinical Medicine Aarhus University Hospital Aarhus Denmark

Princess Maxima Center for Pediatric Oncology Utrecht The Netherlands

University Clermont Auvergne M2iSH UMR1071 Clermont Ferrand France

University Medical Center Utrecht Utrecht The Netherlands

University of Newcastle Newcastle NSW Australia

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Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification